Frank T. Leone

Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma

BACKGROUND Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control. METHODS In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries. RESULTS Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17). CONCLUSIONS Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.)

The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial.

ABSTRACT Objective: To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation. Research design and methods: 320 healthy, motivated-to-quit smokers (≥10 cigarettes/day) aged 18–65 years, entered a multicenter, randomized, double-blind, placebo-controlled study – conducted between December 26, 2001 and June 24, 2003 – with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2–12: 0.5–2.0 mg/day). Main outcome measures: Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward. Results: Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n = 155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p < 0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p < 0.001), 24 (32.5 vs. 13.5%; p < 0.001), and 52 (28.0 vs. 13.5%; p = 0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations. Conclusions: A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation. Trial registration: ClinicalTrials.gov identifier: NCT00150228.

A placebo-controlled trial of modafinil for nicotine dependence

BACKGROUND Nicotine deprivation symptoms, including fatigue and attentional deficits, predict relapse following smoking cessation. Modafinil (Provigil), a wakefulness medication shown to have efficacy for the treatment of cocaine addiction, was tested as a novel therapy for nicotine dependence in a double-blind placebo-controlled trial. METHODS One hundred and fifty-seven treatment-seeking smokers received brief smoking cessation counseling and were randomized to: (1) 8 weeks of modafinil (200mg/day), or (2) 8 weeks of placebo. The primary outcome was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT). Secondary outcomes included cigarette smoking rate and post-quit nicotine deprivation symptoms (e.g., negative affect, withdrawal). RESULTS In this interim study analysis, EOT quit rates did not differ between treatment arms (42% for placebo vs. 34% for modafinil; OR=0.67 [0.34-1.31], p=0.24). Further, from the target quit date to EOT, the daily smoking rate was 44% higher among non-abstainers in the modafinil arm, compared to non-abstainers in the placebo arm (IRR=1.44, CI95=1.09-1.89, p<0.01). Modafinil-treated participants also reported greater increases in negative affect and withdrawal symptoms, vs. participants randomized to placebo (ps<0.05). CONCLUSIONS These data do not support the use of modafinil for the treatment of nicotine dependence and, as a consequence, this trial was discontinued. Cigarette smoking should be considered when modafinil is prescribed, particularly among those with psychiatric conditions that have high comorbidity with nicotine dependence.

Effects of 21 days of varenicline versus placebo on smoking behaviors and urges among non-treatment seeking smokers.

Varenicline promotes smoking cessation and reduces urges to smoke. However, the mechanisms associated with these effects and their time course are not well characterized. One mechanism may be extinction, but the duration of the current dosing protocol may not be sufficient. We examined the effect of extended pre-treatment with varenicline on smoking behavior among 17 non-treatment seeking adult smokers. Using a within-subjects, double-blind, placebo-controlled crossover design, participants received standard dosing of varenicline for 21 days, followed by a 14-day washout period and 21 days of placebo; order counterbalanced. Cigarettes per day (CPD), smoking topography, smoking urges (QSU), and side effects were assessed every three days. Biomarkers (e.g. nicotine metabolites) were collected on days 1, 7, and 21. There was a significant drug by time interaction indicating a reduction in CPD during varenicline phase (between days 10–21), but no reduction during placebo. Varenicline also led to reductions in nicotine metabolites and urges to smoke. Among this sample of non-treatment seeking smokers, varenicline significantly reduced smoking behavior. Results have important treatment implications because changes in CPD and craving did not occur until after the typical one-week run-up period. This suggests that a longer duration of pre-treatment may be beneficial for some smokers.

Nicotine dependence and treatment outcome among African American cocaine-dependent patients

Despite a close association between tobacco and cocaine use, few studies have systematically examined whether smoking predicts an adverse outcome for cocaine-dependent patients. We investigated whether severity of nicotine dependence was related to treatment outcome for cocaine-dependent individuals. Standardized assessments of nicotine dependence (Fagerström Test for Nicotine Dependence; FTND), cocaine use, and personality were obtained for 105 African American cocaine-dependent outpatients. Outcome measures included negative urine drug screens, days in treatment, dropout, and number of treatment sessions attended. The sample was stratified into cocaine-positive and cocaine-negative groups based on admission urine drug screens, and relationships between nicotine dependence and outcome measures were examined in each group. In the cocaine-negative group, higher FTND scores were negatively correlated with number of negative urine drug screens during treatment even after controlling for other predictors, whereas FTND scores were not correlated to outcome in the cocaine-positive group. It seems that severity of tobacco use predicts poor outcome for cocaine-dependent patients who are cocaine free at the time of admission into outpatient treatment.

Developing a Rational Approach to Tobacco Use Treatment in Pulmonary Practice: A Review of the Biological Basis of Nicotine Addiction.

The toll of tobacco use on a pulmonary practice is severe. Physicians, patients, and their families experience frustration, hopelessness, and even anger when confronted with a seemingly irrational decision to keep smoking despite morbid lung disease. This paper examines the biological basis of this behavior and seeks to integrate this insight into a rational approach to the problem in practice. Smoking is reexamined within the framework of an irrational compulsion to seek nicotine, despite a rational desire to stop. Control over the compulsion to smoke is established as an important clinical outcome, and the rationale for treating tobacco dependence as a chronic illness is examined. Finally, practical insights into managing ambivalence, including an aggressive pharmacotherapeutic approach based on the neurobiology, are presented.

The Association between Changes in Alternative Reinforcers and Short-term Smoking Cessation

BACKGROUND While more than 50% of smokers make a serious quit attempt each year, less than 10% quit permanently. Evidence from studies of adolescent smoking and other substances of abuse suggest that alternative reinforcers, a construct of Behavioral Economic Theory, may contribute to the likelihood of smoking cessation in adults. This study examined the behavioral economics of smoking cessation within a smoking cessation clinical trial and evaluated how depressive symptoms and behavioral economic variables are associated with smoking cessation. METHODS A sample of 469 smokers, enrolled in an effectiveness trial that provided counseling and 8 weeks of 21 mg nicotine patches, was analyzed. Alternative reinforcers (substitute and complementary reinforcers) and depressive symptoms were examined in relation to 7-day point prevalence abstinence, verified with breath carbon monoxide, 8 weeks after the quit date. RESULTS Controlling for covariates associated with cessation (nicotine dependence, age of smoking initiation, patch adherence), participants who were abstinent at week 8 showed significantly higher substitute reinforcers at all time-points, compared to those who were smoking (ps<.05). Participants who were abstinent at week 8 showed lower complementary reinforcers and depressive symptoms at all time-points, compared to those who were smoking, but significant differences were confined to week 8 (ps<.01). There was no significant interaction between alternative reinforcers and depressive symptoms across the 8 weeks on week 8 abstinence. CONCLUSIONS These results support continued examination of Behavioral Economic Theory in understanding adult smoking cessation in order to inform future treatments and guidelines.

Predictors of smoking cessation among cancer patients enrolled in a smoking cessation program.

Abstract Many cancer patients continue to smoke postdiagnosis, which is associated with poorer clinical outcomes. Identifying prospective predictors of smoking cessation among patients currently receiving smoking cessation treatment can help guide the development and implementation of smoking cessation programs with this population. Material and methods. Data from 246 cancer patients participating in a randomized placebo-controlled smoking cessation clinical trial were used to examine baseline predictors of end-of-treatment and six-month postbaseline smoking cessation outcomes. Baseline demographic, smoking-related, disease-related, and psychological variables were examined as predictors of biochemically-confirmed point-prevalence abstinence. Results. Multivariate analysis indicated that, for end-of-treatment abstinence, patients were significantly more likely to have quit smoking if they were older (OR = 1.06, 95% CI: 1.03–1.10, p < 0.05) and were diagnosed with a non-tobacco related cancer (OR = 2.54, 95% CI: 1.24–5.20, p < 0.05). Likewise, for six-month abstinence, patients were significantly more likely to have quit smoking if they were older (OR = 1.04, 95% CI: 1.01–1.08, p < 0.05) and were significantly less likely to have quit smoking if they were female (OR = 0.47, 95% CI: 0.22–0.97, p < 0.05). Patients with tobacco-related cancers and female patients reported significantly higher levels of depression symptoms (p < 0.05), which proved predictive of smoking relapse. Conclusions. Patient age, gender, and cancer-type may be important factors to consider when developing and implementing smoking cessation interventions for cancer patients.

Biomarkers to optimize the treatment of nicotine dependence

The application of genomic medicine to the treatment of nicotine dependence holds great promise for revitalizing the steady decline in smoking rates witnessed in the USA over the past several decades. This paper examines the current knowledge base concerning the use of biomarkers to guide the selection of nicotine dependence treatments. First, we review the neurobiology of nicotine dependence and present evidence that supports its heritability. We then discuss the various studies of pharmacokinetic and pharmacodynamic genes related to therapeutic response. Current evidence suggests that biomarkers of genetic variability in both nicotine metabolism, referred to as the nicotine metabolite ratio, and dopamine genotypes may be useful for guiding treatment selection for nicotine dependence. Barriers to the translation of this research to clinical practice are discussed, as are directions for future research.

Symptoms of Depression and Smoking Behaviors Following Treatment with Transdermal Nicotine Patch

Subscales from the Center for Epidemiologic Studies Depression Scale (CESD), assessed prior to treatment, were examined as predictors of withdrawal, craving, and affect during the first week of abstinence, as well as smoking abstinence during the first week of abstinence and at the end of treatment. The negative affect and somatic features CESD subscales were related to higher levels of nicotine withdrawal. The relationship between the interpersonal disturbance CESD subscale and nicotine withdrawal approached significance. This study suggests the need to examine novel psychological mechanisms that may account for the relationship between depression symptoms and smoking cessation.